期刊
JOURNAL OF NEUROSCIENCE
卷 40, 期 45, 页码 8652-8668出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.1636-20.2020
关键词
apoptosis; cortical development; GABAergic interneuron; inhibitory neurons; programmed cell death; Protocadherins
资金
- Scottish Rite Charitable Foundation of Canada [16107]
- Canada Research Chair Tier 2, a Sloan Fellowship in Neuroscience
- Canadian Institutes of Health Research (CIHR) [PJT-148961]
- Canada Research Chair Tier 1
- CIHR [PJT-156034, PJT-156439]
- University of Toronto Open Fellowship
- Restracomp PhD Student award
- Natural Sciences and Engineering Research Council of Canada
- Hospital for Sick Children Restracomp Postdoctoral Fellowship
- Province of Ontario Neurodevelopmental Disorders Programme from the Ontario Brain Institute
Inhibitory interneurons integrate into developing circuits in specific ratios and distributions. In the neocortex, inhibitory network formation occurs concurrently with the apoptotic elimination of a third of GABAergic interneurons. The cell surface molecules that select interneurons to survive or die are unknown. Here, we report that members of the clustered Protocadherins (cPCDHs) control GABAergic interneuron survival during developmentally-regulated cell death. Conditional deletion of the gene cluster encoding the gamma-Protocadherins (Pcdhgs) from developing GABAergic neurons in mice of either sex causes a severe loss of inhibitory populations in multiple brain regions and results in neurologic deficits such as seizures. By focusing on the neocortex and the cerebellar cortex, we demonstrate that reductions of inhibitory interneurons result from elevated apoptosis during the critical postnatal period of programmed cell death (PCD). By contrast, cortical interneuron (cIN) populations are not affected by removal of Pcdhgs from pyramidal neurons or glial cells. Interneuron loss correlates with reduced AKT signaling in Pcdhg mutant interneurons, and is rescued by genetic blockade of the pro-apoptotic factor BAX. Together, these findings identify the PCDHGs as pro-survival transmembrane proteins that select inhibitory interneurons for survival and modulate the extent of PCD. We propose that the PCDHGs contribute to the formation of balanced inhibitory networks by controlling the size of GABAergic interneuron populations in the developing brain.
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